The role of oral nutraceuticals as adjunctive therapy to reduce side effects from isotretinoin: A systematic review
Authors: Ali Shields, Sophia Ly, Bruna Wafae, Yu-Feng Chang, Priya Manjaly, Marjorie Archila, Christina Heinrich, Lara Drake, Arash Mostaghimi, John S. Barbieri
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Although isotretinoin is a highly efficacious acne treatment associated with durable remission, adverse events such as mucocutaneous side effects are common and can result in treatment discontinuation. Since patients may be interested in natural and complementary therapies to alleviate these side effects, this review sought to evaluate the evidence regarding the role of oral nutraceuticals as adjunctive therapy with isotretinoin. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.1Page M.J. McKenzie J.E. Bossuyt P.M. et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021; : n71https://doi.org/10.1136/bmj.n71Crossref PubMed Scopus (25110) Google Scholar It was exempt from institutional review board (IRB) approval. The study was registered with PROSPERO (CRD42022353051). A health sciences librarian (C.H.) performed a search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science databases from inception through January 30, 2023.2Lefebvre C. Glanville J. Briscoe S. et al.Searching for and selecting studies.in: Cochrane Handbook for Systematic Reviews of Interventions. Wiley, 2019: 67-107https://doi.org/10.1002/9781119536604.ch4Crossref Scopus (551) Google Scholar,3Tjosvold L. Randomized Controlled Trials/ Controlled Clinical Trials: A Cut and Paste Search Strategy Adapted from the Cochrane ENT Group for Web of Science. Cochrane ENT Group, 2018Google Scholar We included randomized controlled trials (RCTs) investigating at least 1 oral nutraceutical in patients with acne on isotretinoin. Outcomes of interest were adverse events, skin biophysical parameters, and adherence to treatment. Abstract and full-text screening were conducted by 2 independent reviewers (A.S., S.L., P.M., B.W., Y.C., M.A.). For each of the included articles, study design, nutritional intervention, and outcomes were reviewed. Quality assessment of included trials was performed using the Cochrane Risk of Bias (RoB) Checklist Tool.4Sterne J.A.C. Savović J. Page M.J. et al.RoB 2: a revised tool for assessing risk of bias in randomised trials.BMJ. 2019; 366l4898https://doi.org/10.1136/bmj.l4898Crossref Scopus (10689) Google Scholar Among 2,420 abstracts, 93 full-text articles were assessed for eligibility, with 8 articles (5 fair quality; 3 poor quality) meeting the criteria for inclusion in the review (Fig 1, Table I).Table ICharacteristics and results of included studiesNutraceuticalDosageLength of interventionBlindingOutcomeQualityOmega-31 mg/kg/d12 wkDouble-blindLower rates of cheilitis (32.4%, vs 92.3% P < .01), lip dryness (41.2% vs 73.1%, P = .013) and xerosis (32.4% vs 76.9%, P < .001) in patients who received omega-3 along with isotretinoin compared to placebo.FairOmega-31 g/d16 wkDouble-blindCheilitis (at wk 4, 8 and 12), xerosis (all wk), and dryness of nose (all wk) were significantly (P < .05) less frequent in the group that received omega-3 in addition to their isotretinoin compared to the group that received isotretinoin alone.FairEvening Primrose Oil (EPO)1350 mg/d8 wkSingle-blindProportion of patients presenting with xerotic cheilitis after 2 mo of therapy was significantly lower in the group receiving EPO. The group receiving EPO had a significantly lower score for transepidermal water loss (TEWL) on the lower lip (52.18 vs 70.49, P = .043).PoorEvening Primrose Oil (EPO)2040 mg/d9 moDouble-blindEPO group had a statistically significant increase in skin hydration compared to the isotretinoin only group (8.70 vs −10.5, P < .002) which helped to ameliorate the adverse effects of dryness, lip cracking and peeling skin.FairBiotin10 mg/d9 moUnblindedMean skin hydration decreased in both groups but was found to be significantly lower in the group that only took isotretinoin (P < .001). There was an increase in the TEWL values of both groups, but no significant difference.PoorVitamin E800 IU/d20 wkDouble-blindAdministration of vitamin E did not decrease the average severity, duration, or incidence rates of side effects produced by isotretinoin.FairMulti-ingredient∗Multi-ingredient supplement containing gamma linolenic acid (omega-6), vitamin E, vitamin C, beta-carotene, coenzyme Q10, and "Vitis Vitifera".N/A6 moUnblindedSignificant difference between the 2 groups in the sebum rate (2.4 vs 1.5 P < .0001), hydration (53.2 vs 48.5, P < .0001), and erythema (237 vs 255, P < .0001) in favor of the group taking the dietary supplement.PoorZinc Sulphate1 mg/kg/d20 wkSingle-blindThe frequency of all treatment-related side effects (20% vs 76.7%, P < .001) and the frequency of cheilitis (6.7% vs 43.3, P = .001) was significantly less in the group treated with zinc and low-dose isotretinoin compared to the group treated with standard-dose isotretinoin alone.Fair∗ Multi-ingredient supplement containing gamma linolenic acid (omega-6), vitamin E, vitamin C, beta-carotene, coenzyme Q10, and "Vitis Vitifera". Open table in a new tab Two RCTs found that Omega-3 fatty acids reduced the frequency of mucocutaneous side effects. In a double-blind trial (n = 60), Zainab et al discovered omega-3 (1 mg/kg/day) reduced rates of cheilitis (32.4%, vs 92.3% P < .01), lip dryness (41.2% vs 73.1%, P = .013), and xerosis (32.4% vs 76.9%, P < .001). In a double-blind trial (n = 118), Mirnezami et al found omega-3 (1 g/day) reduced cheilitis, xerosis, and nasal dryness (all P < .05). Two blinded RCTs (n = 40; n = 50) evaluating evening primrose oil, which contains omega-6 fatty acids, found that it was associated with reduced transepidermal water loss (P = .043) and improved skin hydration (P < .002) as well as improvement in xerotic cheilitis (P = .035). A single-blind trial (n = 60) demonstrated that zinc (1 mg/kg/day) with low-dose isotretinoin (0.25 mg/kg/day) had similar efficacy, but reduced overall treatment-related side effects (20% vs 76.7%, P < .001) and cheilitis (6.7% vs 43.3, P = .001) compared to isotretinoin alone (0.5 mg/kg/day) during 20 weeks of treatment. An unblinded RCT (n = 48) found a dietary supplement based on gamma-linolenic acid, vitamins C and E, beta-carotene, coenzyme Q10, and Vitis vinifera (grape seed) improved sebum rate, hydration, and erythema scores (P < .0001). RCTs evaluating vitamin E (n = 140) and biotin (n = 60) did not find benefit. Although studies were small and of limited quality, this review highlights that supplements containing omega-3 fatty acids may be a useful adjunctive strategy to reduce mucocutaneous dryness associated with isotretinoin. Evening primrose oil may also be helpful. Given its potential efficacy for acne, zinc may allow for lower dose isotretinoin regimens and thus reduced side effects.5Cervantes J. Eber A.E. Perper M. Nascimento V.M. Nouri K. Keri J.E. The role of zinc in the treatment of acne: a review of the literature.Dermatol Ther. 2018; 31: e12576https://doi.org/10.1111/dth.12576Crossref Scopus (37) Google Scholar Future studies are required to further evaluate the benefit of these nutraceuticals. Clinicians should be prepared to discuss the potential role of nutraceuticals as adjunctive options for patients being treated with isotretinoin. John S Barbieri has received consulting fees from Dexcel Pharma for work unrelated to the present study. Arash Mostaghimi has received royalty payments from Pfizer for licensing of the ALTO, BELA, and BETA tools and has participated in clinical trials related to alopecia from Incyte, Lilly, Concert, and Aclaris. In addition, Dr Mostaghimi has received consulting fees from Pfizer, Concert, Lilly, AbbVie, hims and hers, Digital Diagnostics, and Bioniz.